This Program Project application was made possible by previous extensive collaborative efforts of investigators who are all involved, in studying the possible role of endothelial cell sin the regulation of vascular function in a variety of tissues in physiological and pathophysiological states. The investigators represent several related research disciplines: Biochemistry, Cell Biology, Physiology and Pharmacology. The common theme among the projects is an interest in the specific biological role of and interaction among locally released mediators from endothelial cells- e.g. eicosanoids, oxygen free radical species and other endothelium dependent vasoactive factors. Many of the participating investigators have been in the forefront of research in this area and their collaboration will provide an impetus to everyone's research effort. We anticipate, that as a result of our coordinated program, the role of endothelial mediators in blood vessel biology as well as their possible role in disease states will become clearer. Project 1 will evaluate a) activation of the epoxygenase/phospholipase A2 pathway in platelets and leukocytes and b) transfer between cells, assimilation, and effect of metabolites of this pathway on endothelial cells and blood vessel function. Project 2 will address the mode of action of reactive oxygen metabolites on regulation of tone in large coronary arteries in vitro as well as the role of endothelial cells in the release of these species. Project 3 will investigate the release of eicosanoids and oxygen radical species from pulmonary endothelial cells and their role in acute lung injury. Project 4 will study in vivo the role and interaction with other endogenous vasoactive agents of endothelium-derived relaxing factor (EDRF) in the control of microvascular function. Project 5 will have as its goal to examine the role, in vivo, of endothelial factors (prostaglandins, EDRF) in the regulation of coronary artery diameter and their contribution to the control of coronary blood flow. Two core facilities will support the research projects: an Administrative core and a Cell Culture Core.